Background. Detection of ≥5 CTC per 7.5 mL of blood before starting systemic treatment is a strong and independent predictor of worse progression-free survival (PFS) and overall survival (OS) in MBC. Trastuzumab (Herceptin®) was shown to be highly effective in reducing CTC number in all HER-2 amplified MBC cases after the first dose (De Giorgi et al., SABCS 2009). Furthermore, trastuzumab can target chemotherapy-resistant CTC in pts with breast cancer (Bozionellou et al. 2004). To date no significant analysis exploring the effect of another anti-HER2 therapy, lapatinib (Tykerb®) on CTC has been published.We hypothesized that anti-HER2-based therapy may modify the detection rate and prognostic value of CTC in pts with HER-2 amplified MBC. Patients and Methods. We retrospectively evaluated 91 HER-2 positive MBC pts, treated at the M. D. Anderson Cancer Center with trastuzumab-based (n=59), or lapatinib-based therapy (n=32). In all pts, CTC were enumerated before starting systemic treatments, using CellSearch™. Follow-up CTC counts were available for 41 (69%) pts treated with trastuzumab and 25 (78%) pts treated with lapatinib. PFS and OS were estimated by Kaplan-Meier product limit, and compared between groups according to baseline CTC count (<5 vs ≥5) by log-rank test. Results. Median follow-up was 27 months (range, 8-65) and 16 months (range, 3-33) for pts receiving trastuzumab and lapatinib, respectively. Treatments administered and CTC counts are reported in table 1. Two (5%) pts receiving trastuzumab and 4 (16%) pts treated with lapatinib had CTC ≥5 at the follow-up assessment. Estimated median PFS and OS according to baseline CTC value, for both treatments are shown in table 2. An elevated CTC count was associated with poor prognosis in pts treated with lapatinib (median OS: 25.8 vs 13.6 months in pts with CTC <5 and ≥5, respectively, P=.072). Surprisingly, in the trastuzumab group, PFS showed a non-statistically significant trend in favor of pts with CTC ≥5 compared to those with <5. Conclusions. According to previously published data, our study confirms that trastuzumab-based therapies can drastically reduce the number of CTC and neutralize their negative prognostic value. Furthermore, we found that lapatinib had a limited effect on the detection rate and prognostic value of CTC, although the low number of pts and the high percentage of pre-treated women do not allow us to draw definitive conclusions. Table 1 Table 2 Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-02-03.
Background: Cytokines and chemokines are known to be involved in tumor growth and progression of disease. Sialyl LewisX (sLeX), a ligand for adhesion molecule E-selectin, is known to affect inflammatory processes and an elevated level is associated with tumor metastasis. Therefore, we assessed serum levels of sLeX and cytokines/chemokines in patients with non-invasive ductal carcinoma in situ (DCIS), early invasive breast cancer (EBC), or metastatic breast cancer (MBC). Patients and Methods: Sera from 250 patients (26 DCIS, 157 EBC, 67 MBC) and 43 healthy donors (HD) were assayed for sLeX using an immunoassay kit (CSLEX; Nittobo Medical Co. Ltd., Japan) and a panel of cytokines and chemokines using a multiplex assay kit. Differences in serum markers between patients and HD, and among patient groups were determined using the Kruskal-Wallis and Mann-Whitney tests. Spearman's correlation determined the non-parametric correlation between the serum levels of sLeX and the inflammatory mediators. The receiver operating characteristic (ROC) curves and the corresponding area under the curve (AUC) analyses were used to determine the sensitivity and specificity of a given cut-off value for a particular serum marker. Results: The median sLeX level tended to increase with the stage of disease: MBC > EBC > DCIS albeit without significant differences among the disease stages. Among MBC patients, patients with sLeX below 1.75 U/mL had significantly improved overall survival (OS, mean survival 11.1 vs. 33.7 months, P = 0.002) and progression-free survival (PFS, mean survival 9.7 vs. 20.9 months, p = 0.042). The Hazard Ratio of high sLeX for OS was 5.5 (95% CI 1.6 to 18.9, p = 0.007) and 2.3 for PFS (95% CI 1.0 to 5.2, P = 0.048). EBC and MBC patients have significantly higher serum levels of IL-1, IL-1RA, IL-6, IL-8, MCP-1, MCP-3, and MIP-1βthan those of HD. In addition, there were positive correlations between the serum levels of sLeX and cytokines IL-1β, IL-1RA, IL-2, IL-8, MIP-1β, and MCP-3. The AUC for sLeX was 0.598 (P = 0.016), and a cut-off of 3.13 pg/mL distinguished hormone receptor (HR)-positive from HR-negative patients (χ2 = 4.0, P = 0.045). Likewise, the AUC for TNF-α was 0.620 (P = 0.003), and a cut-off 7.18 pg/mL distinguished HR-positive from HR-negative patients (χ2 = 12.6, P < 0.001). Using a cut-off value established by ROC curves, few MBC patients (9 of 66, 13.6%) had a serum IL-2 level > 7.1 pg/mL compared to 57 of 185 (30.8%) non-MBC patients (χ2 = 7.4, P = 0.007), suggesting that metastatic disease may be associated with immune suppression related to low serum IL-2. Conversely, 31of 66 (47%) MBC patients had a serum MCP-1 level > 750 pg/mL vs. 37 of 185 non-MBC patients (20%) (χ2 = 23.8, P < 0.0001), suggesting that a high level of MCP-1 may play an important role in metastasis. Conclusion: Serum levels of sLeX were able to distinguish HR-positive from HR-negative patients and predict overall survival in metastatic patients. Serum sLeX and some inflammatory mediators tended to increase with the severity of disease, and together may facilitate local invasion of tumor cells. Furthermore, serum levels of MCP-1 and IL-2 may have prognostic value in breast cancer patients. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-32.
Background Transforming growth factor (TGF)-b1 has pleiotropic effects in cancer. In the early stages of breast cancer, TGF-b may be responsible for immune tolerance through the activation of T-Regulatory cells (TR). On the other hand, in the late stages of disease, it may induce angiogenic factors [vascular endothelial growth factor (VEGF), interleukin-8 (IL-8) (in Bonnomet J Mammary Gland Biol Neoplasia 2010); and IL-17 (Pickens J Immunol 2010)], and epithelial to mesenchymal transition (EMT) which may lead to an increase in the number of circulating tumor cells (CTC) (Kim, Cell 2009). Therefore, we investigated the possible correlation between TGF-b1, CTC count, angiogenic factors and T-cell function of patients with locally advanced or metastatic breast cancer. Methods As an interim analysis of an on-going prospective study, sera and peripheral blood mononuclear cells (PBMC) were collected from breast cancer patients starting a new line of therapy. At analysis, study enrollment included 78 patients with breast cancer [19 with locally advance disease (LABC), 23 with non-metastatic inflammatory breast cancer (IBC), and 32 with metastatic disease (MBC) including 19 with IBC features], and 28 healthy donors (HD). Serum TGF-b1, VEGF, and IL-8 levels were measured by Milliplex Luminex kits (Millipore, Billerica, MA). CD4+CD25+CD127dim TR cells were enumerated in whole blood by FACS (BD Biosciences, San Jose, CA). PBMC were used to study the ability of T cells to synthesize cytokines following activation of the T-cell receptor by immobilized anti-CD3 antibodies. CTC were enumerated by CellSearch (Veridex, Raritan, NJ). The Spearman Rho was calculated for nonparametric correlations and the Mann-Whitney U test was used to determine significant differences between median values. Results LABC patients and HD had a median serum TGF-b1 that was significantly higher than that of MBC patients (P = 0.042). There were statistically significantly positive correlations between serum TGF-b1 and the number of CD4+ T cells (rho = .226, P = .029) and IL-10 produced by %CD4+ (rho = .388, P = .002) and %CD8+ (rho = .459, P < .001) T cells. Furthermore, there was a positive correlation between serum TGF-b1 and the % of CD8+, but not CD4+, T cells that produced IL-17 (rho = .250, P = .022). Serum TGF-b1 levels did not correlate with either % or number of TR cells. Although serum TGF-b1 level of MBC patients was independent of CTCs (24.4 ng/mL vs. 24.0 ng/mL, P = .317), MBC patients with CTC had significantly higher serum levels of angiogenic factors such as VEGF (530 ng/mL vs. 240 ng/mL, P=0.037) and IL-8 (45.6 pg/ml vs. 20.0 pg/ml P= .006) than those of patients with no CTC. Even so, MBC patients with or without CTC have similar % of CD4 and CD8 T-cell subsets that could be activated to produce IFN-g, IL-2, TNF-a, IL-17, or IL-10. Conclusion: The concomitant presence of elevated serum TGF-ß1 levels and IL-10 producing T cells suggest immune suppression could facilitate disease progression of breast cancer. T-cell function is independent of CTC in MBC patients; however, serum VEGF and IL-8 levels were significantly elevated in MBC patients with CTC suggesting that vascular changes can facilitate tumor dissemination. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-02-07.
BACKGROUND: FGFR family members are infrequently mutated but are frequently overexpressed in breast cancer and often accompanied by increased, or altered, expression of FGF ligands. In this retrospective study, we reviewed a large series of FGFR altered breast cancer cases that received comprehensive genomic profiling (CGP) in the course of clinical care. MATERIAL AND METHODS: CGP was performed on hybridization-captures, adaptor ligation-based libraries using DNA extracted from 40 μm formalin-fixed paraffin-embedded (FFPE) section cut at 10 μm performed in a CLIA-certified lab (Foundation Medicine, Inc.). The pathologic diagnosis of each case was confirmed on routine hematoxylin and eosin-stained slides, and all samples forwarded for DNA extraction contained a minimum of 20% of DNA derived from tumor cells. The FoundationOne test sequences the full coding regions of up to 315 cancer-related genes, and up to 28 genes that are frequently altered in cancer to detect all classes of genomic alterations including base substitutions, indels, copy-number alterations (CNA), and fusions/rearrangements. The average depth of coverage is greater than 600X. The genomic profiles of 2,617 patients with diverse advanced malignancies who were evaluated at Cancer Treatment Centers of America between 12/24/12 and 03/11/15 were reviewed. 176 FGFR alterations (7.8%) were detected, of which 76 (43.5%) were found in breast cancer cases out of 434 (16.5%). The study was carried out in accordance with WIRB Institutional Review Board. RESULTS: A total of 76 female breast cancer patients, having a median age 50 (range, 28-69), with FGFR alterations were reviewed. All patients had metastatic/relapsed advanced breast cancer. 54 patients were Estrogen Receptor-positive (70%), and 15 were HER2+ (20%). 6 patients had gBRCA deleterious mutations. 84% of the samples (n=67) tissue block were analyzed, and the anatomic sites represented by the samples were 24 breast primary tumor (31%), 15 liver (19%), 10 lymph nodes (13%), and other sites (37%). The median number of chemotherapies cycles was 4 (range, 1-12), and the median time to metastasis was 31 months (range, 0-175). At the time of this report, 31 patients (40%) were deceased. 79 FGFR gene alterations were identified in 76 patients, including FGFR1 (65), FGFR2 (6), FGFR3 (2), and FGFR4 (4), with all but 7 of these being amplifications. The most co-existent altered gene was TP53 (66%), and other altered genes included PIK3CA (37%), MYC (28%), FGF3/4/19 (17%), CCND1 (17%), and CCNE1 (16%). The subset of co-amplified FGF3/4/19 and FGFR amplified patients were all (7) ER+ except for 1 patient. CONCLUSIONS: FGFR genomic alterations in breast cancer patients are predominantly amplifications and are most commonly observed in ER+ patients. Further review of treatment history will be performed to evaluate the hypothesis that alterations of FGFR is a modifier of response to endocrine therapy, and co-amplified FGF3/4/19 and FGFR breast cancer cases may be a distinct clinic-pathologic entity. Any patients in this series initiated on anti-FGFR targeted therapy will also be reported. Citation Format: Alvarez RH, Thomas JW, Kramer K, Niu J, Ahn E, McKnight JE, Dhillon N, Pabbathi H, Johnson AT, Wang K, Ross JS, Miller VA, Stephens PJ, Daneker GW, Ali S, Markman M. Clinicopathologic characterization and comprehensive genomic profiling (CGP) of advanced breast cancer patients with fibroblast growth factor receptor (FGFR) alterations. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-07-06.
Background: Detection of high number of CTCs (>5) before initiation of first-line therapy in patients with metastatic breast cancer is associated with shorter progression free survival and overall survival. The most widely used method is CellSearch (Veridex, Raritan, NJ). It relies on immunomagnetic capture of CTCs, using antibodies against the epithelial cell adhesion molecule (EpCAM). Although the US Food and Drug Administration approved CellSearch assay for clinical use. In addition to isolation and enumeration, a promising area of research is genomic CTCs characterization which entails phenotyping and molecular expression profiling of CTC subsets consisting of those of epithelial origin (CTC-Epi), others undergoing epithelial to mesenchymal transition (CTC-EMT), or expressing cancer stem cell-like phenotype (CTC-CSC; CD44+ CD24low, ALDH+), respectively. EMT is a molecular process to acquire the traits needed to execute the multiple steps of metastasis. Through the EMT process, epithelial cells lose cell-cell contacts and cell polarity, downregulate epithelial-associated genes, acquire mesenchymal gene expression and undergo major changes in their cytoskeleton. Currently, a CTC detection kit is available to detect CTCs expressing EMT-associated genes by semiquantitative RT-PCR (Adna EMT2/Stem Cell test). EMT will be detected by measuring EMT-inducing transcription factors such as TWIST1, SNAIL1, SLUG, ZEB1 and FOXC2) by RT-PCR Objectives. Primary objective: To investigate if activated pathways in CTCs are correlated with clinical outcome of patient with stage III breast cancer. Secondary objective: To prospectively determine if assessment of the pathways profiling in CTCs can be used to stratify NED breast cancer patients Patients Eligibility: Inclusion: histologically confirmed invasive breast cancer (any subtype), clinical stage III, no evidence of distant metastasis by PET-CT or CT scan of chest and abdomen, and body scan, age 18 years or older, pts must be scheduled to start neoadjuvant/adjuvant therapy, ECOG PS 0-2. Pts must sign a written informed consent. Exclusion: distant metastasis, investigational therapy, prior history of other malignancies within the last 2 years, except non-melanoma skin cancer. This study (PA12-0097) was approved by IRB of UT MD Anderson Cancer Center. Trial Design. This is a pilot, international, multicenter, prospective, blood sample collection from 200 patients with clinical or pathologic stage III breast cancer. Statistical Analysis: This study is a 7-year study (84 months). Pts will be classified as to the presence [negative (neg) vs. positive (pos)] of CTC and as to the expression of a biomarker (neg vs. pos). The primary endpoint of the study is breast cancer recurrence. Time to recurrence curves for the four breast cancer patient groups (neg/neg, neg/pos, pos/neg, or pos/pos) will be estimated using the Kaplan-Meier method and differences in the recurrence rates will be evaluated by the log-rank test at the end of the study (84 months). The confidence intervals for the quantiles of the recurrence distribution will be based on the sign test as described by Brookmeyer and Crowley. Citation Format: Alvarez RH, Gao H, Ensor JE, Gomez HL, Ruiz-Garcia EB, Arce C, Sun H, Willey JS, Ueno NT, Valero V, Reuben JM. Pilot study of prognostic utility of circulating tumor cells (CTCs) assessed by AdnaGen technology and clinical outcome of patients with stage III breast cancer who completed locoregional and systemic treatment. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-02-01.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.